Access valve devices, their use in separation apparatus, and corresponding methods

ABSTRACT

An access valve suitable for controlling fluid flow into and out of a chromatography column has a central axially movable probe with a head acting as a spool valve in a barrel. Axial movement of the probe adjusts the valve between a fully open condition, in which bota first conduit extending through the probe and a second conduit defined around the probe are open to the column interior, a partly open condition in which a second sealing land on the probe closes the second conduit, and a fully closed position in which both conduits are closed. The three positions are useful for packing and unpacking chromatography media into and from the column. In the closed condition of the valve, the first and second conduits communicate with one another so that the valve interior can be cleaned while the column is operating.

FIELD OF THE INVENTION

[0001] This specification relates to methods and apparatus for thecontrol of fluid flow, e.g in chromatography, i.e. apparatus and methodsfor separating substances by passing a mobile phase through a stationaryor retained phase to cause separation of mobile phase components.

BACKGROUND

[0002] Chromatography is a well-established and valuable technique inboth preparative and analytical work as well as in purificationgenerally. Typical industrial chromatography apparatus has an uprighthousing in which a bed of packing material, usually particulate, restsagainst a permeable retaining layer. Fluid mobile phase enters throughan inlet e.g at the top of the column, usually through a porous,perforated, mesh or other restricted-permeability layer, moves throughthe packing bed and is taken out at an outlet, typically below arestricted-permeability layer.

[0003] Changing the bed of packing material, because it is spent or inorder to run a different process, is an arduous task particularly withbig industrial columns which can be hundreds of litres in volume. Theexisting bed has usually become compacted and difficult to remove. Thehousing must be dismantled, the compacted packing mass disrupted andthen removed. Furthermore, the new bed must be very evenly packed if thecolumn is to be effective: the fresh material must be added carefullywhile maintaining a flow of liquid. Usually the apparatus must be keptclean, particularly with biological products where high system sterilitymay be needed for weeks or even months. One small contamination can bedisastrous.

[0004] Conventionally, many hours have been needed to change the spentpacking in a big column.

[0005] GB-A-2258415 describes a column which can be packed and unpackedwithout taking it apart, using special supply and discharge valves inthe top and bottom plates of the housing. The packing supply valve has aspray nozzle which can be retracted into the top plate, with the sprayopenings closed by a seal on the plate, or advanced to project into thecolumn bed space, freeing the openings for a slurry of packing materialto be pumped in. The discharge valve has an advanceable nozzle withradially-directed spray openings at its enlarged head, positionedcoaxially within a wider bore of the bottom plate. When retracted, thehead fits in the bore to seal itself and the bore. To empty the column,the nozzle is advanced and buffer liquid pumped through it. The advancednozzle head breaks up the packed medium and the pumped-in buffer carriesit out through the larger bore, now opened.

[0006] There are difficulties in maintaining long-term sanitaryconditions with these valve assemblies.

THE INVENTION

[0007] We now propose further developments.

[0008] In one aspect we provide separation apparatus having a columnhousing whose housing wall defines an enclosed bed space which in usecontains a bed of packing material. The housing wall includes end wallsat opposite ends (in terms of an operational fluid flow direction) ofthe bed space and having inlet and outlet openings for fluidcommunication to and from the bed space in use. An access valve devicecommunicates with the bed space through the housing wall at an accesslocation. This valve device has first and second adjacent fluid-flowconduits, each having an exterior connection and an interior openingadjacent the housing wall interior. The valve device is controllablyadjustable, from outside the housing wall, between

[0009] a first, closed condition in which the first and second conduitsare both isolated from the bed space;

[0010] a second, partially-open condition in which the device puts thefirst conduit in communication with the bed space but isolates thesecond conduit from the bed space, and

[0011] a third, open condition in which the device puts the first andsecond conduits both in communication with the bed space.

[0012] An access valve of this type offers a number of possibleoperational advantages. Some are described later. One feature it canoffer is packing and unpacking a bed space through a single housing wallinstallation. The relevant processes may be as follows.

[0013] To unpack, the valve is moved to the third condition in whichboth the first and second conduits are open to the bed space. Fluid isforced in through the first conduit to disrupt and disperse the packedbed, the flowable dispersion of the packing material then flowing outthrough the second conduit.

[0014] Preferred features for these purposes include the following.

[0015] The opening of the first conduit may have a spray nozzle or otherrestriction, fixed or adjustable, to help disrupt the bed by flowvelocity. Having plural outlet openings also helps to reach a largerregion of the bed space and clear it more effectively.

[0016] The access valve device preferably comprises a probe which, froma retracted condition recessed into the housing wall, can be advancedinto the bed space to disrupt material therein. The disrupting probe ispreferably a movable valve element defining one or both of the conduits,preferably the first conduit at its outlet (which may be at or throughthe head of the probe e.g. as in GB-A-2258415).

[0017] The opening of the second conduit may form an outlet from the bedspace. Desirably it is a single aperture. Desirably it hascross-sectional area at least a substantial proportion of thecross-sectional flow area within the second conduit itself. Desirablythe cross-sectional area of the second conduit through the valve deviceis generally larger than that of the first conduit.

[0018] To pack, the access valve device can be adjusted to the second,partially-open condition and packing material forced in through thefirst conduit, typically as a dispersion of particles in carrier fluid.Carrier fluid escapes from the bed space through an outlet remote fromthe valve device, while packing material is retained.

[0019] Thus, a bed of new packing material can be packed against apermeable end retainer at a housing wall location spaced from andpreferably opposed to that of the valve device, by maintaining a flow ofcarrier fluid through the accumulating bed and out through the endretainer. This flow of carrier fluid can accompany the injection of bedmaterial through the first conduit.

[0020] The valve device preferably has relatively movable valve parts orelements which are movable in or into face-to-face sealing contact withone another, and defining the first and second conduits. A pair of suchelements may be sufficient to define the first and second conduits andalso sealing portions or lands sufficient for shutting off their inwardopenings for the three conditions mentioned above. Respective spacedsealing portions on one part or element can sealingly engage a singlesealing portion, or plural differently-spaced sealing portions, on theother relatively movable part or element to provide the first and secondconditions.

[0021] The relative movement between the valve elements passing betweenthe three conditions may be linear (typically in the direction throughthe housing wall, preferably perpendicularly), rotational (typicallyaround a direction axis as specified above) or a combination of thesee.g. moved linearly by a screw thread action. The three conditionsdesirably correspond to three spaced stations along a predeterminedsingle rotational, linear or combination (e.g. helical) path or trackfor such relative movement.

[0022] For simplicity one such valve element may have a single sealingland which in the closed condition isolates the first conduit from thebed space and in the partially-open condition isolates the secondconduit from the bed space. This land may be on a said valve elementfixed relative to the housing wall, provided at or adjacent a mouth ofthe valve device. The openings of the first and second conduits can thenbe defined by one or more further valve elements which is/are slidablymoveable relative to that sealing land.

[0023] Valves as proposed above are also usable to govern flow into/outof any vessel or conduit; not only separation apparatus housings.

[0024] It is a particularly desirable feature for a component of aseparator apparatus, and also in other contexts, that it be cleanable inplace (“CIP”) i.e. without removing it from the apparatus and mostpreferably without interfering with the bed space e.g. while separationis in progress.

[0025] In a further aspect we propose that this be achievable, in anaccess valve device governing the communication of first and secondconduits through the housing wall of a separator apparatus bed space asdescribed, or through the well of any vessel or conduit into a space, byarranging that in a closed condition of the valve in which both firstand second conduits are isolated from the space a continuous cleaningpath is defined along the first conduit, through e.g. a cleaning recessin the valve device connecting between the first and second conduits,and along the second conduit. The valve device components are shapedsuch that, for cleaning fluid flow in at least one direction along thecleaning path, all regions thereof are swept i.e. there are no deadspaces. In particular, for at least one said flow direction at no pointin the valve device does the surface of the first conduit, secondconduit or the connecting recess diverge from or converge towards thecentral flow axis (or layer, according to the flow path shape) at aright-angle or greater, and preferably not at an angle greater than 70°.

[0026] One particular proposal provides the possibility of such a flowpath in a three-condition valve device as proposed above, havingrelatively movable valve elements, one of the elements having anisolating seal which seals in the first condition against a firstopposed sealing surface of the other element and in the second conditionseals against a second opposed sealing surface of the other element,isolating the first and second conduits respectively from the bed space.According to our proposal the one valve element defines a recess behindits isolating seal which, in the closed condition, provides clearancearound the second sealing surface of the other element to put the firstand second fluid conduits in communication with one another.

[0027] In separation apparatus, a preferred location for an access valvein any of the aspects described above is in an end wall construction ofthe housing. This end wall is typically fluid-permeable but impermeableto the relevant packing material, e.g. by virtue of a porous, perforatedor mesh layer—a filter layer. The access valve openings open to the bedspace side of this layer. Generally further openings are provided forintroducing fluid material, e.g. a sample or mobile phase generally,behind that filter layer e.g. along a third conduit which extendsthrough the end wall alongside the valve device.

[0028] Another aspect provides uses of an access valve device asdescribed for removing material from a column bed space, and in anadditional version this may be part of a separation process.

[0029] The additional version relates to a separation process in which aliquid incorporating components to be separated is caused to flowupwardly through a bed of particulate stationary phase (packing medium)enclosed in a bed space of a column housing, for example at a rate whichexpands or fluidises the bed. After passing through the bed the liquidpasses a restricted-permeability element (typically a mesh, or a porousor other perforated layer which will retain the packing mediumparticles) and out of the column housing through a process outlet.

[0030] The liquid may incorporate particulate or cohesive matter whichwill not pass, or not freely pass, the restricted-permeability element.Biological culture products are an important example of this. Forinstance, expanded bed separation is used to remove a target protein, byadsorption onto the bed particles, from an unclarified orpartially-clarified culture broth containing cells, cell debris, lipidparticles and/or the like.

[0031] As separation proceeds, such materials accumulate against therestricted-permeability element used to prevent escape of packingmaterial through the process outlet. In time, the accumulated matterprevents effective operation. Processing must be stopped, the columnhousing opened and the accumulated matter cleared before restarting.

[0032] Our proposal is to remove such accumulated matter from the bedspace, e.g. from time to time as the process proceeds, and optionallywithout cutting off the input of feed stock liquid, by

[0033] opening a clearing outlet for accumulated matter at a location ator adjacent the restricted-permeability element and communicatingdirectly with the bed space, and

[0034] forcing a clearing flow of fluid at, across and/or back throughthe restricted-permeability element to disturb the accumulated matter sothat it passes out through the clearing outlet.

[0035] So, the separation process may continue with reduced oreliminated interruptions for clearance of accumulated matter from thebed space.

[0036] The clearing flow may be provided by forcing a reverse flowthrough the restricted-permeability element, e.g. back through theprocess outlet, or through other conduits penetrating the impermeablewall behind the restricted-permeability element. Additionally oralternatively the clearing flow may come through one or more nozzles onthe bed space side of the element by pumping fluid out of them e.g. atthe centre of the element, and desirably with a clearing flow radiatingfrom a conduit penetrating the housing wall.

[0037] These functions may be served by an access valve device asdisclosed in the previous aspects above.

[0038] Another proposal in the context of such a process involves theintroduction of a mobile phase into the column bed space through adirect input opening, preferably valve-governed, rather than through arestricted-permeability element which is provided to retain the inletside of the packing bed. For example, introduction is through an accessvalve device opening through the restricted-permeability element.

[0039] In this way a mobile phase incorporating particulate matter, orother matter which might clog the restricted-permeability element, canbe introduced conveniently into the bed for processing. The access valvedevice used for the introduction may be e.g. any as described above.

[0040] By combining this proposal with the previous one, the introducedparticulate or other matter can then conveniently be cleared from thebed space.

[0041] A further aspect provided herein is a valve device for governingflow through a housing or conduit wall into a space, e.g for achromatography column housing wall. The valve device has an outer barrelelement defining an axial direction. The barrel has an internal boreextending axially from an outer end to an inner end of the barrel, withaxially-directed openings at both ends. The opening at the inner endconstitutes a valve mouth, and provides a radially-inwardly directedmouth sealing surface of the bore.

[0042] An elongate spool element extends axially through the barrel boreand is axially movable relative to it. A central fluid conduit extendsaxially through the spool element, and opens adjacent the barrel mouthpreferably by plural radially-directed openings, preferably as a spraynozzle. The spool element has a first, inner radially-outwardly directedsealing land disposed axially inwardly of the central conduit openingand adapted to seal against the barrel's mouth sealing surface in afirst relative longitudinal position of the spool element relative tothe barrel, thereby isolating the central conduit opening from the valvemouth.

[0043] The spool element also has a second, outer radially-outwardlydirected sealing land disposed axially outwardly of the central conduitopening and adapted to seal against the barrel's mouth sealing surfacein a second, intermediate longitudinal position of the spool elementrelative to the barrel in which the central conduit opening is exposedto the interior space. Outwardly of the second sealing land is aspacing, preferably annular, between the spool element and the barrelbore. This spacing constitutes an outer axially-extending fluid conduitwhich in a second, intermediate position is isolated from the valvemouth by the sealing of the second land.

[0044] In a third, inward position of the spool element relative to thebarrel the second sealing land is clear of the mouth sealing surface andboth the inner and outer conduits are open to the interior.

[0045] This valve device is suitable for use in all of the aboveaspects.

[0046] The barrel bore may have a recess disposed outwardly of the mouthsealing surface and connecting the inner conduit opening to the outerconduit in the fully-closed position.

[0047] The valve may be installed in the wall with the valve mouth atthe wall interior and at the wall exterior a connecting manifoldproviding a fixed communicating connection to the outer conduit at theouter end of the barrel and a movable communicating connection to theinner conduit of the spool element. Means for driving controllablemovement of the spool element is also provided. This may take variousforms which a skilled person can provide without difficulty. Forexample, as disclosed in GB-A-2258415 the spool element may bethread-mounted into the manifold or another fixed component, the drivemeans functioning to rotate it to a controlled extent to give thedesired axial shift.

[0048] In separation apparatus the valve may be installed in an end wallhaving an inner restricted-permeability layer and an outer impermeablewall layer, the valve mouth communicating through therestricted-permeability layer. The outside of the barrel at the mouthmay overlap the restricted-permeability layer to trap it. To introduceprocess fluids into the bed space, one or more process conduits leadthrough the impermeable wall layer to behind the restricted-permeabilitylayer, e.g. alongside the valve barrel as one or more clearances betweenthe valve barrel and the surrounding impermeable layer of the end wall.

BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Embodiments of our proposal are now described in detail, withreference to the accompanying drawings in which

[0050]FIG. 1 is a cross-sectional schematic side view of achromatography column showing the basic features thereof;

[0051]FIG. 2 is an axial cross-section showing an end plate constructionin more detail;

[0052]FIG. 3 shows enlarged, in axial cross-section, the construction ofan access valve;

[0053]FIG. 4 is an axial cross-section corresponding to FIG. 2 with theaccess valve in a part-open position;

[0054]FIG. 5 is an axial cross-section corresponding to FIG. 2 but withthe access valve in a fully-open position;

[0055]FIG. 6 is an axial cross-section of the end plate illustrating amedium packing operation;

[0056]FIG. 7 is a view corresponding to FIG. 6, with the column inoperation and the access valve being cleaned;

[0057]FIG. 8 is an axial cross-section corresponding to FIG. 6illustrating the process of unpacking a packing medium from the column;

[0058]FIG. 9 is an axial cross-section of the top end plate of achromatography column undergoing expanded-bed chromatography,illustrating a clearing operation;

[0059]FIG. 10 is an axial cross-section of a column end which is avariant of that in FIGS. 2 to 8; and

[0060]FIG. 11 is a schematic view of a second version of the accessvalve.

DETAILED DESCRIPTION OF EMBODIMENTS

[0061]FIG. 1 shows schematically the general components of achromatography column 1. The column has a cylindrical fluid-impermeableside wall 11, e.g. of stainless steel or a high-strength/reinforcedpolymeric material which may be translucent. The open top and bottomends of the side wall 11 are closed by top and bottom end assemblies12,13. Each end assembly has a fluid-impermeable end plate 3 fittingsealingly to plug the opening of the cylindrical wall 11, and preferablyof stainless steel or high-strength engineering plastics material, e.gpolypropylene. The end plates are backed up by metal retaining plates 2bearing against their outer surfaces and projecting radially beyond theside wall as retaining flanges 22 through which adjustable tension rods14 are secured. These link the top and end assemblies 12,13 and help theconstruction to withstand high fluid pressures.

[0062] Each end plate 3 has a central through-opening 31 forcommunication between the exterior of the column and the packing bedspace 9 defined by the side wall 11 and end assemblies 12, 13. Accessthrough the opening 31 is subdivided into separate conduits, connectedexternally through a connection manifold 8.

[0063] A filter layer 4, typically of filtered or woven plastics orsteel, extends across the area of the bed space 9 at the inner surfaceof the end plate 3. The inner surface 35 of the end plate 3 is recessedbehind the filter layer 4, e.g. conically as illustrated, and preferablywith the use of support ribs (not indicated) supporting the filter layer4 from behind, to define between them a filtration space 34. One of thecommunication conduits, a mobile phase conduit 33, opens inwardly intothis filtration space 34, as well as outwardly to a mobile phaseconnector 81 of the manifold 8.

[0064] From the manifold 8, an access valve device 5 projects inwardlythrough the end plate opening 31 and sealingly through a central orifice41 of the filter layer 4. The access valve 5, embodiments of which aredescribed in more detail below, governs the communication of one or moreconduits from the manifold 8 directly to the bed space 9, i.e. bypassingthe filter layer 4. Indicated here are first and second valved conduits51, 61 governed by the valve 5, and connected externally throughconnectors 82 of the manifold 8.

[0065] In a typical operation of the column, a packed bed of particulatestationary phase material fills the bed space 9 between the top andbottom filter layers 4. The valve devices 5 being closed, a mobile phaseis fed in through mobile phase connector 81 (arrow “A”), passes throughconduit 33 into the filtration space 34 and through the filter layer 4to elute down through the packed bed, effecting separation of itscomponents. Liquid eluate passes thought the filter layer 4 of thebottom end assembly 13 and out through the mobile phase connector 81thereof (arrow “B”) for collection as appropriate.

[0066]FIG. 1 and the above explanation are to illustrate generalrelationships of components and a typical mode of operation. The skilledperson knows, and it will also appear from the following description,that other specific constructions and modes of operation may beappropriate for different kinds of process.

[0067] A more detailed embodiment of an end plate and valve constructionis now described with reference to FIGS. 2 and 3.

[0068] A manifold 8 is provided as a machined metal or plastics blockfixed sealingly over the central opening 31 of the end plate 3 bythreaded connectors 88, and recessed into a central aperture 23 of anouter metal retaining plate 2 which is fixed to the end plate 3 by bolts21 or other suitable fasteners. The periphery of the end plate 3 sealsagainst the column side wall 11 with an annular polymeric seal member 32which also overlaps the filter layer 4 to retain its periphery. Thisseal member may have an internal rigid reinforcement. Unlike aconventional O-ring it eliminates dead space by sealing with acylindrical surface and mounting in a shape-fitting groove of the endplate.

[0069] The manifold 8 has a central bore 91 coaxial with the plateopening 31 and having inwardly and outwardly directed threadedconnection openings 83, 89. The cylindrical barrel 6 of a spool valve 5is screwed into the inward connection 83, to extend coaxially inwardlythrough the central plate opening 31 and out through a central circularorifice 41 of the filter layer 4, terminating in an outward flange 65which overlaps the filter layer 4. A cylindrical outer sleeve 66 fitssnugly around the barrel 6, its outward edge resting against the inwardface of the manifold block through a polymeric sealing ring 662 and itsinner edge resting against the outer surface of the filter layer 4through another polymeric sealing ring 661, trapping the layer 4 betweenthe sleeve 66 and barrel flange 65. Since the barrel's outer diametercorresponds to that of the layer orifice 41, it is possible in theillustrated condition to remove the barrel by unscrewing it andwithdrawing it inwardly, without disturbing the filter layer 4. This isan advantage for column maintenance.

[0070] One or more flow conduits 33 are created by clearance between thebarrel assembly (barrel and sleeve) and the plate opening 31. Thus, theplate opening 31 may have a plurality of axially-extending channelsdistributed around it to form the conduits 33, intervening surfaces ofthe opening 31 fitting against the barrel assembly. Or, a full annularclearance may be provided. Or, these conduits may be provided away fromthe barrel assembly, defined only through the material of the plate 3.The inner ends of the conduits 33 communicate into the filtration space34. Their outer ends align sealingly (by virtue of polymeric sealingrings 662,663) with connection conduits 811 of the manifold block,connected in common to a threaded or otherwise connectable port 81. Thisestablishes direct fluid communication between filtration space 34 andthe port 81, while communication between the bed space 9 and port 81 isnecessarily through the filter layer 4. Ribs provided on the inner platesurface 35 (in known manner) assist even distribution or collection offluid to or from the space 34.

[0071] A bore 61 extends axially through the barrel 6 from one end tothe other. The bore's outward end merges sealingly (by polymeric sealingring 664) and without change of diameter into the central manifold bore91. The inward end of the bore 6 is on the bed space side of the filterlayer 4, and constitutes a mouth opening 611. The bore 61 has a uniformcylindrical cross-section except for a radially-enlarged portion nearbut outward of the mouth 611. The enlarged portion 612 has a centralcylindrical part bordered on either side by tapering surfaces 613. Theseare angled at not more than 450 from axial.

[0072] A central probe element 7 acts in the bore 61, to give thefunction of a spool valve. The probe element 7 has an elongate tube 72with an open internal bore 73, extending axially from adjacent thebarrel mouth 611 out through the outward end of the barrel 6 and thecoaxial ball 91 of the manifold 8. Outwardly of the outer barrel end, atapered sealing ring 665 seals between the tube 72 and surroundingmanifold ball 91: a plug collar 87 is screwed into the outer connection89 of the manifold to hold the tapered seal 665 effectively in place.

[0073] At its inward end, the probe 7 has a solid head 71 with a pointedtip 74, terminating the bore 73. The head 71 has a cylindrical sealingsurface 711, of the same diameter as the barrel bore 61, and which asshown can seal against an inward sealing surface 64 at the mouth 611 ofthe barrel bore 61, assisted by a flush-recessed polymeric sealing ring641.

[0074] The probe bore 73 opens at a set (FIG. 4) of spray openings 75opening through and distributed circumferentially around the tube 72.The tip sealing surface 711 stands radially proud of these openings 75.Immediately outwardly of the openings the probe head 71 has anotherradially-enlarged portion or land 76 which presents a cylindricalsealing surface 761 bordered by tapering portions 762 angled at not morethan 45° from the axial.

[0075] Outwardly of this second enlargement 76 the tube exterior 72 is aplain cylinder.

[0076] The diameter of the sealing surface 761 on the second enlargement76 is the same as that 711 on the first enlargement 71.

[0077] The tube 72 being narrower than the barrel ball 61, anannular-section clearance 51 is defined between them. This constitutesan outer valve conduit extending out through the outer end of the barrel6 into the manifold bore 91 up to the seal 665, where it diverts to athreaded or otherwise connectable manifold port 82.

[0078] Beyond the manifold 8, the outer end of the probe tube 72 isconnected to means for advancing or retracting it axially relative tothe barrel 6, with sliding through the seal 665. These means may bemotor or servo activated, e.g. advancing the probe 7 by rotating a fixeddrive member which engages the tube 72 via a screw thread, e.g. asproposed in GB-A-2258415. Additionally or alternatively, a manualcontrol is provided for the axial adjustment.

[0079] The spool valve effect of the valve 5 is as follows.

[0080]FIGS. 2 and 3 show a first, closed condition in which the headsealing land 711 seals with the mouth sealing surface 64 of the barrel,isolating both the valve conduits 51, 73 from the bed space 9. Thefiltration conduits 33 are not affected by the valve. The nozzleopenings 75 and the second sealing land 76 register axially with theradially-enlarged portion 612 of the barrel bore 61. This puts thenozzle openings 75 into communication with the outer valve conduit 51,creating a continuous sealingly-enclosed flow path between the probetube bore 73 and the manifold port 82. This path has no unswept areas ordead spaces. Within the valve device 5, none of its boundary surfacesdeviates from the local central flow axis/layer by more than 45°,assisting effective sweeping. In the manifold the path likewise has nodead ends.

[0081] Consequently, when the chromatography column is running (see alsoFIG. 7) the valve device and its associated connections can be cleanedin place by feeding a cleaning solution (e.g. aqueous alkali, or othersuitable cleaning medium known to the art) through that fully-sweepablecleaning path. It is particularly envisaged to feed the cleaningsolution in through the probe tube 72.

[0082]FIG. 4 illustrates a second, partially-open condition of the valve5. The probe tube 72 is advanced sufficiently to bring the secondsealing land 76 into register with the bore mouth 611, where theirrespective sealing surfaces 761, 64 effect a sliding seal. This alsobrings the nozzle openings 75 to outside the mouth 611, communicatingwith the bed space 9. Accordingly the inner valve conduit constituted bythe bore 73 is put into direct communication with the bed space,bypassing the filter layer 4, while the outer valve conduit 51 remainsisolated from the bed space 9.

[0083]FIG. 6 illustrates an application of this in creating a new bed ofpacking material. The packing itself can be as described inGB-A-2258415. Specifically a flowable flurry of packing materialparticles in carrier liquid is pumped in through the tube 72 and spraysout radially in circumferentially-distributed directions from theopenings 75. As packing material accumulates in the bed space 9 excesscarrier fluid escapes through the filter layer 4 and away through thefiltration conduits 33 and manifold port 81, to which a connecting tubeis fastened. This is continued until sufficient packing material hasbeen introduced.

[0084]FIG. 5 illustrates a third condition of the valve. Here the probetube 72 has been advanced further inwardly to bring the second sealingland 76 clear of the mouth seal 64, which now opposes thesmaller-diameter outer surface of the tube 72 to create a clearance,opening the outer valve conduit 51 to the bed space 9 through the mouth611.

[0085]FIG. 8 shows how to exploit this third condition to unpackmaterial from a column bed. It should be noted that, as disclosed inGB-A-2258415, the advanced pointed head 71 of the probe 7 is apt todisrupt existing bed material, which is often a hard compacted mass, andthereby help to initiate unpacking. A carrier liquid such as a buffer ispumped in through the probe bore 73 and out through the nozzle openings75; its high nozzle velocity helps to disrupt and entrain the packedmaterial. The particulate packing material cannot pass the filter layer4, but it can respond to the pumping in of liquid by escaping as aslurry through the mouth 611 of the valve and along the outer valveconduit 51 to the manifold port 82 for discharge along a connected tube.

[0086] So, for the first time a single column wall installation enablesboth packing and unpacking of a column. This can give much greaterflexibility in column operation. Note that the packing and unpackingoperations can be effected entirely from outside the column housing,without needing to dismantle or remove the end assemblies. Furthermorethe valve which can do this can itself be cleaned in place, even whenthe column is running by introducing a mobile phase onto the bed throughthe filtration conduits 33 as shown in FIG. 7. So, even this relativelysophisticated wall installation does not introduce a risk ofcontaminants accumulating and leaching into a long-running processperhaps with disastrous results. In the terminology of the skilledperson in this field, this valve device is a “sanitary” installation.

[0087] Furthermore the valve is easily dismantled for maintenancebecause the probe 7 can be entirely withdrawn inwardly from the barrelbore 61.

[0088] Further modes of use, in relation to expanded-bed separationprocesses, are explained with reference to FIGS. 9 and 10. Expanded bedadsorption is a recently-developed separation technique, particularlyfor reducing or eliminating the need to clarify biological culturesbefore eluting them through a packing to separate out a desiredcomponent. The packing bed is expanded by an upflow of liquid medium sothat even particulate material in the sample can work its way throughthe bed to the outlet above the bed. For expansion the bed must rest ona permeable layer through which the liquid up-flow is established.Introduction of the sample must therefore generally be done as a singlepass, which sample batch then elutes through the bed. Usually desiredmaterials are adsorbed onto the bed particles, and in a subsequent stepare recovered by stopping the liquid up-flow, compressing the bed bymoving down the upper plate and then percolating through the bed aliquid that desorbs the target substance from the bed particles.

[0089] A column for this can have top and bottom retaining assemblieswhich each have an impermeable plate interior filter layer and a centralvalve device as shown in the previous Figures. The normal filtrationconduits and means for establishing up-flow of a mobile phase are alsoprovided.

[0090] A first feature here is that a sample e.g. unclarified broth, canconveniently be introduced into the expanded bed, bypassing the lowerfilter mesh, by injecting it though the inner valve conduit 73 of thelower valve in its second, partially open condition. Where sample isinjected intermittently the lower valve is returned to its fully-closedfirst condition in between. Our new valve construction thereforeprovides a convenient way of introducing such a sample past a meshrequired for maintaining an up-flow.

[0091] A second and very significant feature is explained in relation toFIG. 9, which shows in more detail a top end assembly for theexpanded-bed process.

[0092] During normal running of the process the mobile phase passesthrough the filter layer 4′, through the filtration conduits 33′ andout. There is a gradual accumulation of particulate debris and othermatter reluctant to pass the filter 4′, e.g. lipids. This thereforeaccumulates in an upper bed space region 91 adjacent to filter layer 4′.In time it hinders the maintenance of proper flow.

[0093] By moving the upper valve device 5′ to its third, fully-opencondition for a short period of time, while creating a clearing flow ofliquid adjacent the filter layer 4′ to disturb the accumulated matter,this matter can be caused to follow the clearing flow out of the bedspace via the outer valve conduit 51. One method of achieving a clearingflow is to provide a short blast of suitable liquid, e.g. a buffer,through the probe bore 73′ and out through the nozzle openings 75′ whichare near the filter layer 4′. Alternatively or additionally, the normalflow direction (arrow “X”) of buffer out of the system can temporarilybe reversed and buffer pumped back in through the filtration conduits33′ (arrow “Y”), thereby creating a temporarily downward flow throughthe filter layer 4′ (arrow “Z”), disrupting the accumulated material sothat it can accompany the escape of the temporary liquid pressure waveout through the valve conduit 51. This may be done either with orwithout cut-off of the supply of sample at the bottom of the column.

[0094] Thus, the process can be run as long as the absorption proceedsefficiently, without needing to stop for other reasons. This is a highlyadvantageous procedure.

[0095]FIG. 10 shows a variant end plate construction for achromatography column. The differences from the previous embodimentinclude the following.

[0096] The filter layer 4 is formed integrally with inner and outerannuli 41,42, in one piece in plastics material. The inner annulus 41forms a flush termination for the barrel 6 of the central valve 5, andhas an inwardly-facing surface to form the seal with the valve's centralprobe. This flush one-piece construction further reduces the risk ofcontamination at the point of access. It also enables the filter layer'sinner periphery to self-trap in a groove of the valve barrel 6, enablingthat barrel 6 to be one component rather than two. The end cell andvalve components may be of polypropylene.

[0097] The filter layer's outer annulus 42 is used to hold the filterlayer in place by trapping between the wall 11 of the column and the endplate 3 of the cell, which in this version is a one-piece polypropyleneconstruction.

[0098] The connection manifold 8 has the mobile phase inlet/outlet port81 and the waste slurry outlet port 82 inclined outwardly, rather thanperpendicularly as in the previous embodiment, to improve flow. Afurther significant feature in this embodiment is that the filter layer4 is concave, by virtue of the support ribs on the end plate 3 beingformed with inclined rather than slightly radial edges. We find thatthis slight conicity improves drainage from the column during clearing.

[0099]FIG. 11 shows schematically a different embodiment valve whichhowever embodies similar concepts. Here the central movable probe is asimple armature rather than a fluid-carrying nozzle. Its enlarged head171 is carried on actuating rod 272 and has a flat end surface 1712, afirst outer sealing land 1711, a conical convergence 1613 to a narrowrecess or waist 1612, and a smaller enlargement 176 with a secondsealing surface 1761.

[0100] The mobile phase conduit 33 is provide outside the valve barrel 6as before. Inside the valve barrel the central fluid conduit 173 isdefined not through the probe 272,171 but rather by an inner conduitwall 172 surrounding the probe shaft 272 and having an opening with aninwardly-directed seal 174, recessed back from the main opening throughthe filter layer 4, which has its own inwardly-directed seal 141 at themouth of the outer conduit defined between the outer barrel wall 6 andthe inner conduit wall 172.

[0101]FIG. 11 shows the valve fully open, with the central probe fullyadvanced to open both conduits e.g for unpacking and column. Unpackingliquid is pumped in through the inner conduit 173 and squirts out aroundthe armature head 171; waste slurry flows back and out through the outerconduit.

[0102] In the partially open position, e.g for packing a column, thearmature is partially retracted so that second sealing surface 1761seals off the inner conduit, the outer conduit remaining open. Slurrycan be pumped in through the outer conduit. This shears the slurry lessthan the spray nozzle of the first embodiment.

[0103] Full retraction of the armature brings its front surface 1712flush with the filter layer 4 and its first head sealing surface 1711into sealing engagement with the central filter opening seal 141,closing off the outer conduit. At the same time the second sealing land176 drops below the inner conduit seal 174 which then opposes the recess1612 to permit a circulating, clean-in-place flow through the inner andouter conduits.

[0104] Note that in the open conditions the conical portion 1613 of thehead 171 can be axially adjusted to alter the direction of liquid pumpedin. This embodiment illustrates how two separate seals on the fixed partof the valve can provide the same effect as previously if their spacingis different from that of the corresponding sealing portions of themovable part.

1. A separation process for separating a target component from a liquidincorporating the target component with one or more other components,the separation process comprising providing a bed of particulate packingmedium, said medium being adapted to retain the target component andsaid bed thereof being enclosed in a bed space defined by a columnhousing, said housing having a process outlet and a restrictedpermeability element between the process outlet and bed space to retainthe particulate packing medium in the bed space; flowing liquid upwardlythrough the bed of particulate packing medium, through therestricted-permeability element and through the process outlet, toexpand the bed in the bed space and effect separation of the targetcomponent from the liquid through retention by the particulate packingmedium; said one or more other components of the liquid comprisingparticulate matter, said particulate matter accumulating against therestricted-permeability element during the flowing of the liquid, andthe process further comprising opening a clearing outlet communicatingdirectly with the bed space, at or adjacent the restricted-permeabilityelement, and forcing a clearing flow of fluid relative to the restrictedpermeability element to disturb the particulate matter which hasaccumulated against it, and causing said matter to pass out of the bedspace through the clearing outlet.
 2. A separation process as claimed inclaim 1, in which the liquid comprises unclarified orpartially-clarified cell culture broth, and the target component is aprotein product in the culture broth.
 3. A separation process as claimedin claim 1 in which the clearing flow comprises a reverse flow forcedback through the restricted permeability element.
 4. A separationprocess as claimed in claim 3, wherein said reverse flow travels throughsaid process outlet and communicates directly with the bed space bypassing through said restricted permeability element.
 5. A separationprocess as claimed in claim 1 in which a said clearing flow is forcedthrough at least one nozzle at the bed space side of therestricted-permeability element.
 6. A separation process as claimed inclaim 5 in which a said nozzle is on a conduit at the centre of therestricted-permeability outlet, and the clearing flow radiates from thenozzle.
 7. A separation process as claimed in claim 5 wherein theclearing flow includes passing flow through said at least one nozzle andalso through a channel defined by said process outlet.
 8. A separationprocess according to claim 1 comprising flowing liquid upwardly throughthe bed of a particulate packing material concurrently with the flow ofthe clearing flow.
 9. A separation process as claimed in claim 1 inwhich the column housing has a housing wall and an access valve isprovided through the housing wall and restricted-permeability element toenable communication of first and second fluid flow conduits directlyinto the bed space, said access valve being adjustable between a closedcondition in which said conduits are isolated from the bed space and anopen condition in which said conduits are open to the bed space; saidaccess valve being adjusted in the process to the open positionwhereupon said second fluid flow conduit provides the clearing outletand a said clearing flow of fluid is introduced through the first fluidflow conduit.
 10. A separation process as claimed in claim 1 in whichthe column housing has an inlet-side restricted-permeability element andsaid flowing comprises pumping liquid medium through the inlet-siderestricted-permeability element to expand the bed, and an inlet-sideaccess valve movable between open and closed conditions is provided tocommunicate directly with the bed space, a material containing saidtarget component being introduced directly into the bed space throughsaid inlet-side access valve in its open condition.
 11. A separationprocess as defined in claim 10 in which said material comprises anunclarified or partially-clarified culture broth, and the targetcomponent is a protein product in the culture broth.
 12. A separationprocess as claimed in claim 10 in which the inlet-side access valveopens at the center of the inlet-side restricted permeability element.13. A separation process for separating a target component from a liquidincorporating the target component with one or more other components,the separation process comprising providing a bed of particulate packingmedium, said medium being adapted to retain the target component andsaid bed thereof being enclosed in a bed space defined by a columnhousing, said housing having a process inlet, an inlet-siderestricted-permeability element separating the bed space from theprocess inlet, a process outlet, an outlet-side restricted-permeabilityelement separating the bed space from the process outlet, saidrestricted-permeability elements retaining the particulate packingmedium in the bed space; introducing a flow of liquid through theprocess inlet and upwardly through the inlet-siderestricted-permeability element, through the bed of particulate packingmedium to expand the bed in the bed space, through the outlet-siderestricted-permeability element and through the process outlet, andintroducing a mobile phase material containing the target componentdirectly into the bed space through a valved input opening.
 14. Aseparation process as claimed in claim 13 in which the input opening isthrough an access valve device extending through the inlet-siderestricted-permeability element.
 15. A separation process as claimed inclaim 13 in which the mobile phase material incorporates particulatematter.
 16. A separation process according to claim 15 in which themobile phase material comprises unclarified or partially-clarifiedculture broth and the target component is a protein product in saidbroth.